Exposure to cold and draught, alcohol consumption, and the NS

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Occup Environ Med 2001;58:160–164
Exposure to cold and draught, alcohol
consumption, and the NS-phenotype are
associated with chronic bronchitis: an
epidemiological investigation of 3387 men aged
53–75 years: the Copenhagen Male Study
P Suadicani, H O Hein, H W Meyer, F Gyntelberg
H:S Bispebjerg
Hospital, University of
Copenhagen,
Epidemiological
Research Unit, Clinic
of Occupational and
Environmental
Medicine, Bispebjerg
Bakke 23, 2400
Copenhagen NV,
Denmark
P Suadicani
H O Hein
H W Meyer
F Gyntelberg
H:S Glostrup Hospital,
University of
Copenhagen, The
Glostrup Population
Studies, Department
of Internal Medicine
C, Glostrup, Denmark
H O Hein
Correspondence to:
Dr P Suadicani
[email protected]
Accepted 14 November 2000
Abstract
Objectives—This study was performed to
estimate the strength of association between chronic bronchitis and lifetime
exposure to occupational factors, current
lifestyle, and the NS-phenotype in the
MNS blood group among middle aged and
elderly men.
Methods—The study was carried out
within the frameworks of the Copenhagen
Male Study. Of 3387 men 3331 men with a
mean age of 63 (range 53–75) years could
be classified by prevalence of chronic
bronchitis. As well as the completion of a
large questionnaire on health, lifestyle,
and working conditions, all participants
had a thorough examination, including
measurements of height and weight and
blood pressure and a venous blood sample
was taken for the measurement of serum
cotinine and MNS typing; 16.5% of the
men had the NS-phenotype. Chronic
bronchitis was defined as cough and
phlegm lasting 3 months or more for at
least 2 years; 14.6% had chronic bronchitis.
Results—Smoking and smoke inhalation
were the factors most strongly associated
with prevalence of chronic bronchitis.
There were three major new findings: (a)
long term (>5 years) occupational exposure to cold and draught was associated
with a significantly increased prevalence
of chronic bronchitis; compared with others, and adjusted for confounders, the
odds ratio (OR) with 95% confidence
interval (95% CI) was 1.4 (1.1 to 1.7),
p=0.004; (b) a significant J shaped association existed between alcohol use and
bronchitis, p<0.001, with the lowest prevalence found among moderate users; (c) a
significant gene by environment association existed between smoking and the
NS-phenotype in the MNS blood group;
only among smokers was the NSphenotype associated with a significantly
decreased risk of chronic bronchitis, OR
0.67 (0.47-0.97), p=0.02. Other well known
associations between dust, fumes, and
even exposure to solvents and bronchitis
were confirmed.
Conclusion—The results emphasise the
multifactorial nature of chronic bronchitis, and show some hitherto unrecognised
www.occenvmed.com
associations between cold and draught
exposure, alcohol consumption, and the
NS-phenotype and chronic bronchitis.
(Occup Environ Med 2001;58:160–164)
Keywords: alcohol; chronic bronchitis; cold; draught;
genetic marker; MNS; occupational exposure
Based on results from studies of non-selected
populations1–7 and occupational cohorts,8–11 it
has been established that smoking, exposure to
dust, and exposure to fumes and solvents are
associated with risk of chronic bronchitis; the
literature on lifestyle factors and environmental
exposures has been reviewed by Higgins12 and
by Garshick et al.13
Genetic factors also have been implicated in
the aetiology of chronic bronchitis. In a recent
review article, Sandford et al stated that only a
few genes have been investigated as potential
risk factors for chronic bronchitis.5 Homozygosity for the Z allele of the á1-antitrypsin gene
has been established as a risk factor, and
heterozygotes for the Z allele may be at
increased risk. Other mutations aVecting the
structure of á1-antitrypsin or the regulation of
gene expression have been identified as risk
factors. Genes, including those for á1antichymotrypsin, á2-macroglobulin, vitamin
D binding protein, and blood group antigens
have been associated with the development of
bronchitis—for example, in the Copenhagen
Male Study.14 Among more than 3000 middle
aged and elderly men there was a significant,
heterogenous association between the MNS
phenotypes and prevalence of chronic bronchitis, with the lowest prevalence found in men
with the NS-phenotype.
The strength of the association between lifestyle and environmental factors and chronic
bronchitis may depend on genetics. Despite
this, the importance of the interplay of genetic
and environmental factors has not, to our
knowledge, previously been studied in nonselected populations. This study of middle
aged and elderly men was performed to (a)
estimate the relative strength of association
between chronic bronchitis and occupational
and lifestyle factors and the NS-phenotype;
and, (b) to test if the risk associated with identified occupational and lifestyle factors was
modified by the NS-phenotype.
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161
Cold and draught, alcohol, and the NS-phenotype and chronic bronchitis
Table 1 Genetic, lifestyle, clinical, and sociodemographic characteristics of men with and
without chronic bronchitis
NS-phenotype in MNS blood group:
Overall (%)
Among smokers (%)
Lifestyle factors:
Alcohol use:
Abstention (%)
Moderate (1–21 drinks/week) (%)
More than moderate (22–35 drinks/week) (%)
Heavy use (>35 drinks/day) (%)
Low physical activity, <4 h/week (%)
Smoking (%)
Smokers only:
Inhalation (%)
Amount smoked (g/day)
Clinical or paraclinical variables:
Peak flow (l/min)
Height (cm)
Weight (kg)
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
Serum cotinine (ng/ml)
Smokers only:
Serum cotinine (ng/ml)
Other characteristics:
Low social class (classes IV and V) (%)
Retired (%)
Age (y, mean (SD))
Bronchitis
n=485
No bronchitis
n=2846
13.6
12.7
17.0
17.4
12
51
21
16
52
80
11
60
19
10
47
51
0.532
<0.001
0.145
<0.001
0.088
<0.001
82
17.2 (8.0)
72
14.9 (7.8)
<0.001
<0.001
412 (125)
173 (6)
76 (12)
118 (16)
71 (13)
327 (227)
504 (87)
174 (6)
78 (11)
122 (17)
73 (12)
197 (234)
<0.001
<0.001
0.009
<0.001
<0.001
<0.001
392 (194)
343 (201)
<0.001
59
54
63.2 (5.2)
51
47.5
62.8 (5.2)
<0.001
0.003
0.175
p Value
0.073
0.033
Values are means (SD) or frequencies (%). p Values are of Student’s t test (for continuous variables
other than peak flow), Mann-Whitney rank sum analysis (for peak flow), or Yates corrected ÷2
analysis (for categorical variables).
Subjects and methods
The Copenhagen Male Study15 was set up in
1970 as a prospective cardiovascular cohort
study of 5249 men with a mean age of 48 years
(range 40–59). In 1985–6 a new baseline was
established. All survivors from the 1970 study
were traced through the Danish Central Population Register. Between June 1985 and June
1986 all survivors (except 34 emigrants) from
the original cohort were invited to take part in
this study: 3387 (75%) agreed and gave
informed consent. Their mean age was 63
(range 53–74) years.
The 1985–6 study took place at Glostrup
Hospital, University of Copenhagen. Each
subject was interviewed (by HOH) about a
previously completed questionnaire and then
had a clinical examination.
QUESTIONNAIRE INFORMATION
Several questions were asked on previous
occupational exposure. Each question on
exposure was phrased “Have you been exposed
often—that is, several times a week–to exposure at your current or former jobs?.” The
answer options were yes, no, and, if yes, for how
Table 2 Relative strength of association with chronic bronchitis of genetic, lifestyle, clinical,
and sociodemographic characteristics
Smoking v not
Inhalation v not
Alcohol use, diVerent categories referencing abstainers:
Moderate use (1–21 drinks/week):
More than moderate (22–35 drinks/week):
Heavy use (>35 drinks/week):
Retired v not
Systolic blood pressure (mm Hg, risk associated with a one
unit change)
Height (cm, risk associated with a one unit change)
NS-phenotype v others
OR (95% CI)
p Value
2.5 (1.8 to 3.4)
1.7 (1.3 to 2.3)
<0.001
<0.001
<0.001
0.8 (0.6 to 1.1)
1.1 (0.7 to 1.6)
1.4 (0.95 to 2.1)
1.4 (1.1 to 1.7)
0.99 (0.98 to 0.997)
0.002
0.002
0.98 (0.96 to 0.99)
0.7 (0.6 to 0.99)
0.004
0.038
Not in the final model (p>0.10): social class, weight, age.
Variables are ordered according to statistical strength of association with bronchitis after
multivariate adjustment in a logistic regression model with backward elimination of variables.
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many years? For most analytical purposes
occupational exposures were dichotomised at
more than 5 years of exposure.
Based on a slightly modified version of the
British Medical Research Council questionnaire on respiratory symptoms16 the men were
classified as having chronic bronchitis or not.
Chronic bronchitis was defined as cough and
phlegm lasting 3 months or more for at least 2
years. Of 3331 participants with useful questionnaire information on relevant items, 485
(14.6%) were classified as having chronic
bronchitis.
Total weekly alcohol consumption was calculated from items about average alcohol consumption on weekdays and at weekends.
Intakes of beer, wine, and spirits were reported
separately, and most of the alcohol consumed
was beer. One drink corresponded to about
12 g ethanol. The men classified themselves as
never smokers, previous smokers, or current
smokers. Current tobacco consumption was
calculated from information about the number
of cigarettes, cheroots, cigars, or the weight of
pipe tobacco smoked daily. One cigarette was
taken as equivalent to 1 g tobacco, one cheroot
as 3 g tobacco, and one cigar as 4 g tobacco. To
validate the tobacco information serum cotinine was measured with a radioimmunoassay
(RIA) method at Medi-Lab, Copenhagen. As
previously estimated by means of measurements of serum cotinine, the validity of tobacco
reporting was high.17 The men classified themselves for leisure time physical activity as either
sedentary, slightly active—less than 2 hours a
week—or physically more active.
CLINICAL EXAMINATION
A clinical examination included measurement
of peak expiratory flow with a WrightMcKerrow peak flow meter, and measurements of height, weight, and blood pressure;
blood pressure was measured on the right arm
with the subject seated, by means of the
manometer developed by the London School
of Hygiene.18 A venous blood sample was taken
for MNS typing and measurements of cotinine
concentrations after the subject had fasted for
at least 12 hours. The typing was carried out on
red cells with conventional haemagglutination
techniques; 16.5% of the men had the
NS-phenotype.
SOCIAL CLASS
The men were classified into five social classes
based on a modification of the system of
Svalastoga,19 which involved level of education
and job profile.20 Strata were defined as follows:
class I, self employed subjects with at least 21
employees, white collar workers with at least 51
subordinates, or subjects with an academic
degree; class II, self employed subjects with
6–20 employees, white collar workers with
11–50 subordinates, or subjects with an
intermediate education; class III, self employed
subjects with 1–5 employees and white collar
workers with 1–10 subordinates; class IV, self
employed subjects without employees, white
collar workers without subordinates or without
qualified work, and skilled blue collar workers;
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Suadicani, Hein, Meyer, et al
Table 3 Association between chronic bronchitis and relevant occupational long term
exposure (>5 y) to physical and chemical factors
Exposure
Chronic bronchitis
n=485 (%)
No bronchitis
n=2846 (%)
p Value
Cold and draught
Strong variations of temperature
Strong heat
Moist and humidity
Dust (concrete, granite, etc)
Asbestos
Soldering fumes
Welding fumes
Organic solvents
Vapours from lacquer, paint, varnish
Plastic (manufacture of or exposure to vapours)
Glass fibre
60
40
15
14
13
7
10
13
16
8
2.7
2.5
49
31
11
10
8
4
9
9
10
6
1.1
1.6
<0.001
<0.001
0.024
0.010
<0.001
0.004
0.447
0.020
<0.001
0.125
0.011
0.145
p Values are of Yates’s corrected ÷2 tests. Variables are presented according to their order in the
questionnaire.
class V, unskilled blue collar workers. Typical
jobs in the study cohort were; in social class I
oYcer, civil engineer, oYce executive, head of
department; social class II head clerk, engineer,
non-academic architect; social class III engine
driver, train guard; social class IV machine fitter in a telephone company, station foreman;
social class V unskilled labourer, mechanic, or
driver. For presentation purposes social class
was divided into two groups: low social class
(classes IV and V) and high social class (classes
I, II, and III).
ETHICS
Each participant was informed that all personal
data were confidential, and gave written
consent about participation. The study was
approved by the ethics committee for medical
research in the County of Copenhagen.
STATISTICS
Basic analyses comprising Student’s t test, ÷2
analyses, and the regression analyses, were performed with the SPSS statistical software for
Windows.21 22 Odds ratios were calculated by
taking the natural loge raised to the regression
coeYcient for the variable of interest in a multiple logistic regression model with stepwise
backward elimination of variables and the
maximum likelihood ratio method.23 Whether a
forward stepwise, a backward stepwise, or a
forced entry approach was used, did not materially change the association between covariates and the prevalence of chronic bronchitis.
Multiplicative interaction terms between
groups of genetic risk and lifestyle, occupational exposures, and clinical characteristics,
were included in a final analysis to test whether
the risk associated with identified lifestyle and
other factors was modified by genetic factors.
The rationale of the method has been deTable 4 Relative strength of association between chronic bronchitis and long term
occupational exposure to physical and chemical factors adjusted for social class and age
Cold and draught exposure v not
Dust exposure v not
Social class IV/V v I, II, III
Organic solvent exposure v not
OR (95% CI)
p Value
1.4 (1.1 to 1.7)
1.5 (1.1 to 2.0)
1.2 (0.99 to 1.5)
1.3 (0.99 to 1.8)
0.002
0.020
0.063
0.066
Not in the final model (p>0.10): age, plastic (manufacture of or exposure to vapours), strong variations of temperature, strong heat, moist and humidity, asbestos, soldering fumes, welding fumes,
vapours (from lacquer, paint, and varnish), glass fibre.
Variables are ordered according to strength of association with bronchitis after multivariate
adjustment in a logistic regression model with backward elimination of variables.
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scribed by Kleinbaum et al.24 All risk factor
covariates in the regression analyses were those
measured in 1985–6. In the multivariate analyses we used the program default allowing variables with p values <0.10 to remain in the
adjusted model.
Results
Table 1 shows the distribution of genetic, clinical, and sociodemographic characteristics in
men with and without chronic bronchitis.
Apart from lower peak flow values in men with
bronchitis, the most pronounced diVerences
were found for smoking, but also alcohol consumption was associated with the prevalence of
bronchitis; moderate consumption had a lower
prevalence and heavy consumption had a
higher prevalence of chronic bronchitis. Men
with bronchitis were less physically active,
belonged to lower social classes, and were more
often retired. The NS-phenotype was more
often present in men without bronchitis, with a
significantly stronger association among smokers. Moreover, men with bronchitis were of
shorter stature, had a lower blood pressure, and
weighed less than men without bronchitis.
Table 2 shows the results of a multivariate
analysis including relevant factors presented in
table 1. Positively associated with chronic
bronchitis were current smoking, smoke inhalation, and being retired; negative associations
were found with blood pressure, height, and
the NS-phenotype, and a J shaped association
was found with alcohol consumption. Social
class, weight, and age were not in the final
model.
Table 3 shows the association between
potentially relevant occupational long term
exposures to physical and chemical factors and
prevalence of chronic bronchitis. All the listed
factors were more prevalent among men with
bronchitis. The factors were either of a climatic
nature or related to exposure to dust, fumes,
and organic solvents.
The relative strength of association between
chronic bronchitis and long term occupational
exposure to physical and chemical factors after
multivariate analysis is shown in table 4. The
strongest factor was long term exposure to cold
and draughts, but also exposure to organic solvents and dust remained in the statistical model
even when adjustment was made for social
class. The odds ratios of occupational exposures associated with bronchitis in the adjusted
multivariate model ranged between 1.3 and
1.5.
Table 5 shows the relative strength of association between chronic bronchitis and relevant
genetic, lifestyle, clinical, and sociodemographic characteristics, and relevant occupational exposures after adjustment in the
multivariate model. Smoking and smoke inhalation were the strongest discriminatory factors, but occupational exposure to cold and
draught, organic solvents and dust, and the
NS-phenotype were also significant covariates
of bronchitis. Other factors significantly characterising subjects with chronic bronchitis were
blood pressure, age, height, and alcohol
consumption. With the same factors as covari-
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163
Cold and draught, alcohol, and the NS-phenotype and chronic bronchitis
Table 5 Relative strength of association with chronic bronchitis of relevant genetic, lifestyle, clinical, sociodemographic
characteristics, and relevant occupational exposures
Smoking v not
Inhalation v not
Age (y, risk associated with a one unit change)
Alcohol use, diVerent categories referencing abstainers:
Moderate use (1–21 drinks/week)
More than moderate (22–35 drinks/week)
Heavy use (>35 drinks/week)
Systolic blood pressure (mm Hg, risk associated with a one
unit change)
Long term exposure to cold and draught exposure v not
Long term exposure to organic solvents v not
Height (cm, risk associated with a one unit change)
Long term dust exposure v not
NS-phenotype v others
OR (95% CI)
p Value
2.4 (1.7 to 3.4)
1.7 (1.3 to 2.4)
1.04 (1.02 to 1.06)
<0.001
<0.001
0.002
0.003
0.8 (0.6 to 1.1)
1.1 (0.7 to 1.6)
1.5 (0.96 to 2.2)
0.99 (0.98 to 0.997)
0.003
1.4 (1.1 to 1.7)
1.5 (1.1 to 2.1)
0.98 (0.96 to 0.997)
1.5 (1.1 to 2.1)
0.7 (0.5 to 0.999)
0.004
0.008
0.019
0.025
0.044
Not in the final model (p>0.10): weight, retirement status, social class.
Variables are ordered according to strength of association with bronchitis after multivariate adjustment in a logistic regression model
with backward elimination of variables.
n = 237
ates in analysis of smokers only, compared with
men with other phenotypes, the odds ratio
(95% confidence interval) of men with the
NS-phenotype was 0.67 (0.47 to 0.97), p=0.02
(not shown in table 5).
In an additional multivariate analysis we
included the same factors as in table 5 together
with interaction terms (between NS-phenotype
and the other factors which remained in the
final model in table 5 (not shown)). Of interaction terms, only the interaction between
NS-phenotype and smoking was significantly
n = 467
n = 87
n = 249
n = 1244
15
n = 70
%
20
n = 46
n = 357
Others
25
10
n = 86
NS-phenotype
30
n = 378
35
5
0
0
1–10
11–15
>21
16–20
Tobacco smoked/day (g)
0
0
1
n = 384
n = 112
n = 328
n = 416
n = 118
10
n = 357
20
n = 404
%
2–3
n = 88
n = 228
n = 367
1
30
n = 107
Adverse occupational
factors
0
40
n = 251
Figure 1 Prevalence of chronic bronchitis by MNS phenotype and amount of tobacco
smoked/day.
2
3
Adverse life style factors (n)
Figure 2 Prevalence of chronic bronchitis by number of adverse lifestyle factors (not
moderate alcohol use, smoking, inhalation) and adverse occupational factors (long term
exposure to cold and draught, dust, organic solvents).
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associated with bronchitis, p=0.02. The interplay of the NS-phenotype, current smoking,
and prevalence of chronic bronchitis is shown
in figure 1.
Figure 2 depicts the interplay of lifestyle factors, occupational exposures, and prevalence of
chronic bronchitis; occupational factors were
positively associated with the prevalence of
chronic bronchitis irrespective of the number
of adverse lifestyle factors characterising the
group.
Discussion
This study showed that occupational, lifestyle,
and genetic factors were independently associated with chronic bronchitis. There were three
major new findings: (a) an increased prevalence of bronchitis among men who had been
occupationally exposed to cold and draught for
more than 5 years, (b) a J shaped association
between alcohol consumption and prevalence
of chronic bronchitis, and (c) a significant gene
by environment association between smoking
and the NS-phenotype in the MNS blood
group. Established and less established independent associations between smoking, exposure to dust, and exposure to solvents and
chronic bronchitis were confirmed, as were the
well known inverse associations between systemic arterial blood pressure and height and
chronic bronchitis.25 26
In cross sectional studies with retrospective
data it is necessary to consider potential bias, in
particular bias related to measurements, inadequate confounder control, and selection.
Would such sources of bias be able to explain
the associations found?
Definition of chronic bronchitis was based
on conventional criteria of the British Medical
Research Council questionnaire for determining bronchitis. Recognised laboratory methods
were used to ascertain genetic markers, and the
distribution of MNS phenotypes was in agreement with previous studies on Danes.27 Information on smoking was validated by measuring
serum cotinine. Data on occupational exposure
were based on self assessment. However, previous studies in the Copenhagen Male Study
have shown a strong agreement between job
titles and exposures likely to be associated with
specific job functions.28 Despite this, impreci-
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164
Suadicani, Hein, Meyer, et al
sion in the validity of exposure and outcome
variables, and of potential confounders, cannot
be excluded. It seems unlikely that this would
be responsible for our findings, rather the
strength of the associations found may have
been underestimated. Selection bias is another
potential problem. Chronic bronchitis is no
rare cause of death, and severe bronchitis may
further handicap a potential study participant,
so that he would be less likely to attend the
study. Measurement bias seems unlikely, but
selection bias could not have been responsible
for our findings, as selection phenomena would
tend to obscure genuine associations. Finally, a
comprehensive confounder control was carried
out, so that inadequate control for the impact
of major confounders also seems an unlikely
explanation for our findings.
Are the new findings biologically plausible?
Chronic bronchitis is primarily an inflammatory condition involving various immune responses. As reviewed by Shephard29 exposure
to various environmental stressors, including
cold, may impair the human response to infections by modifying various components of
immune function such as T cell count, natural
killer cell counts, cytolytic activity, cytokine
secretion, lymphocyte proliferation, and immunoglobulin concentrations. An immunological
mechanism caused by exposure to cold and
draught therefore seems likely.
An immunological mechanism related to the
MNS blood group is also likely. The MNS
phenotypes are involved in the function of
immunoglobulins,30 and is therefore at least
one biologically plausible mechanism for the
association found between the NS-phenotype
blood group and chronic bronchitis. The finding is furthermore interesting in the light of
findings made in the field of carcinogenesis that
individual susceptibility to carcinogens may be
particularly important at low environmental
exposures.31 This agrees with the finding that,
in this study, the apparently protective eVect of
the NS-phenotype vanished at high exposures
to tobacco.
The J shaped association between alcohol
consumption and bronchitis is interesting in
the light of the well known association between
bronchitis and risk of ischaemic heart disease,
and the well known J or U shaped association
between alcohol consumption and risk of
ischaemic heart disease.32 Previous studies on
lung function and haemostatic factors have
shown an increased concentration of plasma
fibrinogen in subjects with bronchitis, and one
of the mechanisms whereby alcohol is supposed to lower risk of heart disease is through
its lowering of fibrinogen.33
In conclusion, the results of this study
emphasise the multifactorial nature of chronic
bronchitis, and show some hitherto unrecognised associations between exposure to cold
and draughts, alcohol consumption, and the
NS-phenotype and chronic bronchitis.
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Downloaded from http://oem.bmj.com/ on June 18, 2017 - Published by group.bmj.com
Exposure to cold and draught, alcohol
consumption, and the NS-phenotype are
associated with chronic bronchitis: an
epidemiological investigation of 3387 men aged
53 −75 years: the Copenhagen Male Study
P Suadicani, H O Hein, H W Meyer and F Gyntelberg
Occup Environ Med 2001 58: 160-164
doi: 10.1136/oem.58.3.160
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